Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer-related deaths in women in the United States and the leading cause of gynecologic cancer related deaths (Jemal A, Siegel et. al, Cancer statistics, 2007, CA Cancer J Clin 2007; 57:43-66). Annually, there are more than 22,000 new cases of ovarian cancer in the United States and over 16,000 deaths. Despite efforts to develop an effective ovarian cancer screening method, most patients still present with advanced (Stages III-IV) disease. Survival of patients diagnosed with ovarian cancer is known to closely correlate with stage at diagnosis.
Treatment for advanced ovarian carcinoma is based on the combination of surgery and chemotherapy. The objective of surgical intervention in patients suffering from advanced disease is to perform cytoreduction to minimal residual disease in the abdominal cavity. Surgery is followed by adjuvant platinum based chemotherapy. The two most important prognostic factors for patients with advanced ovarian carcinoma are the amount of residual disease left after surgery and the response to platinum based chemotherapy.
Platinum-based cytotoxic chemotherapy in conjunction with debulking surgery is currently the gold standard treatment for patients with ovarian cancer. Although 80-90% of patients initially respond to first line treatment, most will either later progress during therapy or recur after complete remission. Patients who have a prolonged disease-free-interval after first line platinum based chemotherapy, are usually rechallenged with platinum and are more likely to respond well to second line therapy. This group of patients has an improved prognosis with a prolonged disease free interval and longer overall survival. Patients who have progressive disease during platinum treatment or who suffer first recurrent disease within a short period of time are termed platinum-resistant. These patients are given alternative chemotherapy regimens who offer relatively small total response rates reaching 20-30% at most. They will usually have a poorer prognosis.
Comparison of the patterns of gene expressions in ovarian cancer and normal ovarian tissue using cDNA micro-arrays revealed several genes that are under- or over-expressed in ovarian cancer (Collins Y, et al. Int J Mol Med 2004; 14:43-53). Patterns of gene expression that predict response to chemotherapeutic agents and prognosis have also been identified.
microRNAs (miRNAs, miRs) are endogenous non-coding small RNAs that interfere with the translation of coding messenger RNAs (mRNAs) in a sequence specific manner, playing a critical role in the control of gene expression during development and tissue homeostasis (Yi et al., 2006, Nat Genet 38, 356-362). Certain miRNAs have been shown to be deregulated in human cancer, and their specific over- or under-expression has been shown to correlate with particular tumor types (Calin and Croce, 2006, Nat Rev Cancer 6, 857-866), as well as to predict patient outcome (Yu et al., 2008, Cancer Cell 13, 48-57). In some cases miRNA overexpression results in reduced expression of tumor suppressor genes, while loss of miRNA expression often leads to oncogene activation.
Thus, there exists a need to identify biomarkers that will make it possible to detect and predict which patients with ovarian cancer will respond to platinum based chemotherapy and which patients will remain refractory to this treatment. Specific data may assist in tailoring treatment to each patient's specific clinical situation during initial management of their disease and also offer the opportunity for better counseling regarding prognosis.